Sudden Cardiac Death (SCD) is often attributed to ventricular fibrillation, a lethal arrhythmia that results in uncoordinated contraction of the heart. Experiments have demonstrated that the cardiac myocyte electrical excitability can be reduced or eliminated during conditions of ischemia and reperfusion. The mechanism involves a series of failures in myocyte function, in which increased production of reactive oxygen species (ROS) during conditions of metabolic stress reduces or even eliminates myocyte excitability. Experimental evidence has demonstrated that these inexcitable regions within the myocardium could block propagation of electrical excitation. However, how the 3D distribution of metabolically-stressed regions affects the electrophysiological behavior of the heart remains unknown. Utilizing multi-scale integrated metabolic and electrophysiological whole heart models could provide an opportunity to dissect the mechanisms for arrhythmia generation under the conditions of ischemia and reperfusion. The overall objective of this research is to address the ways in which coupling between metabolic and electrophysiological processes in the whole heart contribute to the risk of arrhythmia under ischemia and reperfusion. To achieve this objective, I will develop and validate, from magnetic resonance imaging (MRI) and diffusion-tensor magnetic resonance imaging (DTMRI), electrophysiological recordings, and mitochondrial metabolic data, novel biophysically-, metabolically- and anatomically-detailed computational models of electrical conduction in whole guinea pig hearts. These models will be used to test the hypothesis that the metabolic sinks (regions of metabolically- induced inexcitability) promote reentry and thus contribute to the generation of arrhythmia. The development of a validated realistic model of metabolic and electrophysiological processes under ischemia and reperfusion overcomes the inability of current experimental techniques to simultaneously record the 3D electrical and metabolic activity of the heart with high spatial and temporal resolution. The new insights gained from this study are expected to ultimately lead to improvement in the selection criteria for identifying ICD candidates, and in the development of novel diagnostic and therapeutic procedures for combating arrhythmias. This relates to the NHLBI mission to support basic research that investigates the causes and treatments of heart disease. The specific aims are as follows 1) Use MRI and DTMRI to reconstruct the geometry, fiber and sheet orientation of guinea pig hearts. Combine the imaging data, electrophysiological recordings, and mitochondrial bioenergetics data, to develop and validate electrically and metabolically coupled detailed high-resolution 3D computational models of guinea pig hearts. 2) Using the computational models developed under Specific Aim 1;investigate the mechanisms by which regional mitochondrial uncoupling under the conditions of ischemia- reperfusion results in the formation of reentrant circuits in the guinea pig heart. PUBLIC HEALTH RELEVANCE: This research will help explain how the metabolic and electrophysiological processes in the heart contribute to the risk of arrhythmia under ischemia/reperfusion. The insights gained from this research will ultimately help better identify candidates for implantable cardioverter defibrillators and develop new strategies for combating arrhythmias.